Glaucoma is one of the leading causes of blindness in America, and disproportionately affects African Americans. This grant is focused on finding POAG susceptibility genes in this understudied population. POAG causes blindness through death of the retinal ganglion cells and degeneration of the optic nerve, often accompanied by elevated intraocular pressure. There is a large genetic component to this disease, but the specific genes involved are not yet known. During the first funding period of this grant, we investigated gene expression in the trabecular meshwork and the retina by generating over 800,000 Serial Analysis of Gene Expression (SAGE) tags. We hypothesize that the genes expressed in these tissues constitute excellent candidates for POAG susceptibility genes. We have just completed linkage analysis in 142 multiplex POAG families using over 5,000 single nucleotide polymorphisms. Analysis of this screen identified one novel linkage peak on Chromosome 3 in African Americans with a non-parametric linkage score greater than 3.0. It also identified a second African American linkage peak on chromosome 2 that replicates a previously identified locus in a Barbados population with a lod score of 3.5. We now propose to follow up these two linkage peaks to identify the causative POAG susceptibility genes. We will use a two-pronged attack to find these genes. First we will use a genomic convergence approach that takes advantage of multiple types of data including linkage, association, expression, and biological pathway analysis. Second, we will use a traditional association mapping approach to characterize these two regions. The identification of POAG susceptibility genes could provide the basis for diagnostic tests and lead to earlier detection of POAG and a greatly improved prognosis for the millions of patients affected with this blinding disease.